Cellulose acetate pthalate (CAP) possesses many of the desirable features of a topical microbicide for prevention of HIV-1 infections in humans, foremost of which is its anti-viral activity in vitro. However, the less than complete protection conferred by a CAP topical cream against vaginal transmission of the simian immunodeficiency virus (SIV) in rhesus macaques raises certain important issues that need to be addressed as part of its development. The applicant hypothesizes that distribution and/or epithelial changes induced by CAP affect its efficacy. Furthermore, structural as well as functional differences in the envelope glycoproteins of HIV and SIV may limit the translation of the finding in the SIV/macaque model to that of the human setting. For these reasons, the applicant proposes to conduct detailed irritation and distribution studies of CAP in rhesus macaques and to assess the protective effect conferred by CAP against vaginal challenge with pathogenic SHIVs. SHIVs are simian/human chimeric viruses in which the env, tat and rev genes of the pathogenic SIVmac239 strain were replaced with their corresponding HIV counterparts. SHIVs that carry the envelopes of CXCR4 (X4) and CCR5 (R5) HIV-1 viruses have been developed and shown to cause disease in naive animals when inoculated intravenously or mucosally. Thus, infection of macaques with X4 and R5 SHIVs provides a range of pathogenesis, cellular involvement and coreceptor usages that parallel HIV infection and disease in humans, and is probably one of the best models available to assess the protective effect of CAP. Three specific aims are proposed. (1) Assess the safety of CAP cream in vivo. Colposcopy as well as measurement of pro-inflammatory chemokines and cytokines will be performed to assess the effect of CAP cream on the vaginal epithelium of rhesus macaques. (2) Assess CAP distribution in vivo by colposcopy and magnetic resonance imaging. (3) Evaluate the protective effect of CAP against challenge with pathogenic X4 and R5 SHIVs. Results from the proposed studies should establish the safety as well as efficacy of CAP in vivo.